The search for antibacterial agents began in the late 1800s with the realization that “germs” caused human disease. Over the past century scientists have developed a variety of drugs useful in the targeting and inhibition of numerous bacterial strains. In particular, antibacterial agents known as antibiotics have been developed and are in common use throughout the industrialized world to treat most known bacterial infections. Originally, antibiotics like penicillin inhibited replication of bacteria by blocking the action of transpeptidase, an enzyme responsible for the building of bacterial cell walls. However, due to overuse and resistance adaptations of many bacterial strains, many antibiotics have lost some or all of their effectiveness at treating infection. A line of antibacterial agents that target new molecular growth mechanisms would be useful in avoidance of further enhancement of antibiotic resistance. One such target is tRNA synthetase.
tRNA synthetases are involved in protein biosynthesis so that inhibition thereof may be expected to lead to a cessation of cell growth. Thus, for instance, the compound mupirocin, produced by the organism Pseudomonas fluorescents, is an antibacterial agent and is used as the active ingredient in the product Bactroban®, marketed by GlaxoSmithKline. Mupirocin has been shown to be an inhibitor of the isoleucyl tRNA synthetase. Each tRNA synthetase represents a separate target for drug discovery. tRNA synthetase inhibitors which are selective for bacterial cells over mammalian cells are of considerable therapeutic interest as they have the potential to be used as antibacterial agents in the treatment of human disease.
The sequence of the tRNA synthetase genes in the Gram positive organism S. aureus have recently been determined (see, for instance, European Patent application no 97300317.1, SmithKline Beecham, for S. aureus MetRS), thereby assisting the process of identifying inhibitors. In addition, the sequence of tRNA synthetase genes in other pathogenic bacteria, for instance the Gram negative organism H. influenzae, has also been published (R. D. Fleischmann et al., Science, 269, 496-512, 1995).
Several compounds have recently been disclosed for their inhibitory activity toward methionyl tRNA synthetase (MetRS) and for their capacity as antibacterial agents. In particular, Jarvest et al. described various bicyclic heteroaromatic compounds that have shown MetRS inhibition. (Bioorg. & Med. Chem. Lett. 14 (2004) 3937-3941). In light of these findings there continues to be a need in the art to identify and utilize compounds that target MetRS and thereby provide new approaches for the treatment of infectious disease.
One particularly interesting bacterial target is the organism Clostridium difficile (C. difficile). C. difficile is becoming a more prevalent infectious agent, where one to three percent of healthy individuals are carriers of the organism. (Bartlett & Perl, N. Engl. J Med., 353, 2503-2505, 2005; Clabots et al., J Infect. Dis., 166, 561-567, 1992; McFarland et al., N. Engl. J Med., 320, 204-210, 1989). The risk of infection and disease becomes increasingly prevalent in the immunodeficient, elderly, and especially to the elderly in healthcare settings, e.g., nursing home, hospital, doctors office, etc. Few conventional antibacterial drugs have shown promise in the treatment of C. difficile, in fact only vancomycin is approved by the FDA for treatment of C. difficile associated diarrhea (CDAD) (C. difficile has shown surprising resistance to conventional antibiotic treatment, often flourishing in the gut of individuals under treatment). As such, there is a need in the art to obtain additional approaches for the treatment of C. difficile based infection, especially treatments that avoid conventional antibiotic treatments and therefore antibiotic resistance.
Against this backdrop the present invention has been discovered.